Pantoprazole cyclodextrin inclusion complexes

ABSTRACT

An inclusion complex formed from pantoprazole and cyclodextrin is described.

TECHNICAL FIELD

The present Invention relates to the field of pharmaceutical technologyand describes pantoprazole cyclodextrin inclusion complexes.

BACKGROUND ART

H⁺/K⁺-ATPase inhibitors, in particularpyridin-2-ylmethylsulfinyl-1H-benzimidazoles like those disclosed, forexample, in EP-A-0 005 129, EP-A-0 166 287, EP-A-0 174 726 and EP-A-0268 956 are important In the therapy of disorders originating fromincreased gastric acid secretion. Examples of active ingredients fromthis group which are commercially available are5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: omeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: pantoprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: lansoprazole) and2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(INN: rabeprazole).

WO86/00913 discloses to form a stable complex by mixing and reactingomeprazole with β-cyclodextrin In 96% ethanol and cooling the reactant.WO93/13138 is related to a method for preparing enteric coated oraldrugs containing acid-unstable compound, in particular an enteric-coatedoral drug prepared in the form of acid-stable dosage unit inclusioncomplex formed by reacting benzimidazole derivative, acid-unstablecompound, with cyclodextrin in alkaline solution. WO9638175 is relatedto a stabilized composition comprising an antiulcerative benzimidazolecompound, particularly a proton pump inhibitor and a branchedcyclodextrinic carboxylic acid. WO99/62958 is related to alkylatedcyclodextrin derivates and their use as carriers for medicaments.WO98/40069 describes pharmaceutical formulations comprising abenzimidazole and as excipients, at least one cyclodextrin and at leastone amino acid. EP-A-1018340 discloses the simultaneous reaction of abenzimidazole derivative with one or more amino acids and one or morecyclodextrins as a process to obtain an inclusion complex of a salt of abenzimidazole derivative.

DESCRIPTION OF THE INVENTION

Surprisingly it has now been found that by reaction of pantoprazole witha cyclodextrin, inclusion complexes are obtained with increased overallsolubility for pantoprazole brought about by the formation of solublepantoprazole-cyclodextrin complexes.

Subject of the present invention is a pantoprazole cyclodextrinInclusion complex.

Pantoprazole in connection with the invention refers to5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole.Pantoprazole is a chiral compound. The term pantoprazole in connectionwith the invention also encompasses the pure enantiomers of pantoprazoleand their mixtures in any mixing ratio. Pure enantiomers which may bementioned by way of example are (−)-pantoprazole and (+)-pantoprazole.Pantoprazole may be present as such or, preferably, in the form of itssalts with bases. Examples of salts with bases which may be mentionedare sodium, potassium, magnesium or calcium salts. In a preferredembodiment pantoprazole refers to pantoprazole sodium or pantoprazolemagnesium. If pantoprazole is isolated in crystalline form, it maycontain variable amounts of solvent. The term pantoprazole thereforealso represents according to the invention all solvates, in particularall hydrates, of pantoprazole and its salts.

In a preferred embodiment pantoprazole refers to pantoprazole sodiumsesquihydrate (=pantoprazole sodium×1.5 H₂O), (−)-pantoprazole sodiumsesquihydrate or pantoprazole magnesium dihydrate.

Cyclodextrin in connection with the invention preferably refers to α-,β- or γ-cyclodextrin, their hydrates, mixtures of α-, β- orγ-cyclodextrin or derivatives of α-, β- or γ-cyclodextrin such as alkylor hydroxyalkyl derivatives. In a preferred embodiment of the inventioncyclodextrin refers to β-cyclodextrin (β-CD),hydroxypropyl-β-cyclodextrin (HPβ-CD), the sodium salt ofsulfobutylether β-cyclodextrin (SBβ-CD) or hydroxyethyl-β-cyclodextrin.

In a preferred embodiment according to the invention the pantoprazolecyclodextrin inclusion complex refers to a 1/1(pantoprazole/cyclodextrin) complex. The pantoprazole cyclodextrininclusion complexes may be produced for example by standard proceduresfor preparation of compound-cyclodextrin inclusion complexes. Suchprocedures are for example disclosed in WO86/00913, WO93/13138,WO96/38175 or by Duchene (in Proceedings of the Fourth InternationalSymposium on Cyclodextrines, 265-275, 1988 by Kluwer AcademicPublishers; eds. O. Huber and J. Szejtli). Inclusion compounds areusually prepared in liquid medium, but they can also be obtained in thesolid phase. In one embodiment of the invention the inclusion complex isobtained by reacting pantoprazole with the cyclodextrin in a suitablesolvent. In a preferred embodiment of the invention the solvent is anaqueous solvent or a solvent which essentially consists of an aliphaticalcohol, preferably ethanol. The inclusion complex may then be obtainedby precipitation or freeze drying. In one embodiment the inclusioncomplex is obtained according to the method described in WO86/00913.

The pantoprazole cyclodextrin inclusion complexes of the invention canthen be used as a basis for the production of the administration formsaccording to the invention. Administration forms according to theinvention which may be mentioned, to which the preparations can beprocessed, are, for example, suspensions, gels, tablets, coated tablets,multicomponent tablets, effervescent tablets, rapidly disintegratingtablets, powders in sachets, sugar-coated tablets, capsules oralternatively suppositories. The excipients which are suitable for thedesired administration forms are familiar to the person skilled in theart on the basis of his/her expert knowledge. Due to the increasedsolubility of pantoprazole In the pantoprazole cyclodextrin inclusioncomplex administration forms containing such inclusion complex haveimproved active compound bloavailability properties.

Suitable administration forms are for example disclosed in WO92/22284,WO97/02020, EP-A-0 244 380, WO96/01623, WO96/01624, WO96/01625 orWO97/25030.

The administration forms (also referred to as pharmaceuticalformulations) according to the invention comprise the pantoprazole ofpantoprazole cyclodextrin inclusion complex in the dose customary forthe treatment of the particular disorder. The pantoprazole cyclodextrininclusion complex of the invention can be employed for the treatment andprevention of all disorders which are regarded as treatable orpreventable by the use of pyridin-2-ylmethylsulfinyl-1 H-benzimidazoles.In particular, the pantoprazole cyclodextrin inclusion complex of theinvention can be employed for the treatment or prophylaxis of gastricdisorders such as peptic ulcer disease or other disorders associatedwith gastric hyperacidity such as gastro-oesophagal reflux disease,Zollinger-Ellison Syndrome and dyspepsia (see e.g. MARTINDALE—Thecomplete Drug Reference, Pantoprazole, MICROMEDEX® Healthcare SeriesVol. 113, 2002). Administration forms such as tablets contain between 1and 500 mg, preferably between 5 and 60 mg, of an acid-labile protonpump inhibitor. Examples which may be mentioned are tablets whichcontain 10, 20, 40 or 50 mg of pantoprazole. The daily dose (e.g. 40 mgof active ingredient) can be administered, for example, in the form of asingle dose or by means of a plurality of doses of the tablets of theinvention (e.g. 2×20 mg of active ingredient).

EXAMPLE5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazoleSodium Sesquihydrate β-cyclodextrin Inclusion Complex

1.73 g of5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazolesodium sesquihydrate, 5.67 g β-cyclodextrin and 20 ml of ethanol (96%)are heated to 30 to 32° C. and stirred for 15 hours. The mixtures iscooled to 10° C. within 3 hours, filtered and the precipitate washedwith ethanol (10° C.). After drying under reduced pressure the titlecompound is obtained.

Complexation Studies of Pantoprazole with Cyclodextrins

Methods: Various solutions of the different cyclodextrins taken intoconsideration were prepared in phosphate buffer solution pH 7 at knownconcentrations and used to create saturated solutions of pantoprazole.After equilibration, these saturated solutions were filtered through MF™membrane filters (pore size 0.45 μm), appropriately diluted withphosphate buffer solution and subjected to uv/vis spectrophotometricanalysis. The cyclodextrin solutions prepared with phosphate bufferranged from concentrations of 0% p/v up to 1.8% p/v for βCD, 20% p/v forHPβCD.

Results: In both cases, the solubility of pantoprazole increasedmarkedly with increasing cyclodextrin concentration. In the presence ofβCD pantoprazole's solubility rose to a four fold maximum with respectto its solubility in phosphate buffer whereas when equilibrated withHPβCD, pantoprazole showed an outstanding increase in its solubilityreaching over seventy times that in phosphate buffer solution.

Conclusions: The phase solubility studies with βCD and HPβCD were bothcharacterised by an over-all increase in pantoprazole's solubilitybrought about by the formation of soluble pantoprazole/cyclodextrincomplexes. In the case of βCD phase solubility studies, the increaseobserved followed a typical A_(p) pattern commonly described byHiguchi-Connor, indicating the formation of complexes with an orderhigher than one. Pantoprazole's behaviour with HPβCD also followed atypical Higuchi-Connor's A_(p) pattern characterised further by aninitially gradual increase in solubility.

Complexation studies on pantoprazole, both in its saline form as asodium salt (PNTNa) and as a free acid (PNTH), were carried out withβ-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HPβ-CD) and thesodium salt of sulfobutylether β-cyclodextrin (SBβ-CD). A second studywas carried to define the Phase-solubility behaviour of PNTH whenequilibrated with aqueous solutions of β-CD, HPβ-CD and SBβ-CD preparedin phosphate buffer solution (pH 7).

Methods of Sample Preparation Preparation of PNTH

Pantoprazole sodium salt was used as a starting material. PNTH wasobtained via drop by drop acidification of an aqueous solution of thesodium salt with acetic acid (0.1 N) until pH 7.5 was reached. Theresulting milky white suspension was filtered with use of the Buchnerapparatus and the resulting solid was left to dry.

Complexation Studies

Kneading

Inclusion complexes of pantoprazole, both the sodium salt (PNTNa) andthe undissociated form (PNTH), with β-cyclodextrin (β-CD),hydroxypropyl-β-cyclodextrin (HPβ-CD) and the sodium salt ofsulfobutylether β-cyclodextrin (SBβ-CD) were prepared via kneading 1:1and 1:2 molar physical mixtures. A phosphate buffer or a 1:1hydroethanolic solution were used as binding solutions respectively forthe preparation of the inclusion complexes of PNNa and PNTH.

Freeze Drying

The technique of Freeze-Drying was applied to the preparation of 1:1molar inclusion complexes of PNTH and PNTNa respectively with HPβ-CD.

In preparing the PNTNa: HPβ-CD 1:1 molar sample, which was then to besubjected to freeze drying, the exact quantity of HPβ-CD was firstdissolved in the minimum amount of distilled water necessary (1.5 ml/mgca) and stirred continuously. The exact amount of weighed PNTNa was thenadded in small portions. After complete solubilization of the drug, thesample was frozen in liquid nitrogen and freeze dried (−70° C., 760torr) for 12 hours.

The PNTH: HPβ-CD 1:1 molar sample was prepared differently according tothe following method. Once again, the exact quantity of HPβ-CD was firstdissolved in the minimum amount of distilled water necessary (1.5 ml/mgca) and stirred continuously. The exact amount of weighed PNTH was thenadded in small portions but its solubilization was helped along by theaddition of acetone. The total volume of acetone added in relation tothe amount of water used to solubilize HPβ-CD was 1:1. The sample wasthen frozen in liquid nitrogen and freeze dried (−70° C., 760 torr) for12 hours.

Phase-Solubility Studies of PNTH with Natural and Modified Cyclodextrins

The Solubility of PNTH in Phosphate Buffer Solution at pH 7 wasDetermined Using a Previously Constructed Asorbance vs. ConcentrationCalibration Curve.

A known amount of PNTH was suspended in cyclodextrin solutions ofdifferent concentrations ranging from; 0 to 1.8% (p/v) for β-CD, 0 to20% (p/v) for H-Pβ-CD and 0 to 15% (p/v) for SB-β-CD. The resultingsuspension was filtered using a PTFE 0.45μ filter, adequately dilutedand then subjected to UV spectrophotometric analysis. The concentrationof PNTH in the corresponding sample was then calculated referring to therelevant PNTH calibration curve.

Characterization Techniques

Complexation Studies

Thermal traces were obtained using a Mettler DSC 821 ⁶ module. FTIRspectra were carried out on KBr discs in the 400-4000 cm⁻¹ range (JascoFT-300-IE). The Freeze Dryer used was a Pirani 10 Edwards Modulyo model.Powder X-ray diffractograms were recorded using a Bruker D5005Diffractometer.

Phase-Solubility Studies

UV-VIS spectra were recorded on a Jasco V570 Spectrophoto meter.

Results

Phase-Solubility Studies

A. Phase-Solubility Curve of PNTH with β-CD in Phosphate Buffer SolutionpH 7.

The Phase-solubility curve (FIG. 1) follows a typical Higuchi-Connorpattern of type A_(L). In fact, pantoprazole presents a linear increasein its apparent solubility when equilibrated with solutions of β-CD,reaching up to four times its solubility in phosphate buffer alone (from0.56 mmol/L up to 2.25 mmol/L).

B. Phase-Solubility Curve of PNTH with HPβ-CD In Phosphate BufferSolution pH 7

Even in this case, the Phase Solubility curve (FIG. 2) follows atypically linear Higuchi-Connor pattern. In fact, the increase observedin the apparent solubility of pantoprazole when equilibrated withsolutions of HPβ-CD, reaches up to 36 times that in phosphate bufferalone (from 0.56 mmol/L up to 17.8 mmol/L).

C. Phase-Solubility Curve of PNTH with SBβ-CD in Phosphate BufferSolution pH 7

In this case, the solubility of pantoprazole increases linearly whenequilibrated with solutions of SBβ-CD, and the Phase Solubility curve(FIG. 3) shows that its apparent solubility increases twenty fold withrespect to its value in phosphate buffer alone (from 0.56 mmol/L up to9.3 mmol/L).

Complexation Studies of Samples Prepared by Kneading

Differential Scanning Calorimetry (DSC) was first used to characteriseboth the physical mixtures and the solid phases obtained after wettingand kneading. In none of the cases did we succeed in obtaining anInclusion complex using the technique of kneading. In fact, the DSCtraces showed a first broad endothermic peak below 100° C. correspondingto cyclodextrin dehydration, and a second sharp endothermic peak eitherat 134° C. for PNTNa or at 144° C. for PNTH due to fusion.

Complexation Studies of Samples Prepared via Freeze Drying

The samples obtained via freeze drying both had a fluffy white foam-likeconsistancy. Thermal analysis of these samples demonstrated, by theabsence of the characteristic endothermic peaks of fusion of PNTNa andPNTH, that complexation had effectively occurred. The PNTH-HPβ-CD 1:1inclusion complex was extremely deliquescent. Powder X-raydiffractograms of the PNTNa: HPβ-CD 1:1 inclusion compound proved it tohave an amorphous solid structure.

CONCLUSIONS

1) Phase-solubility studies have shown that with all three CDs used, anotable increase in the apparent solubility of PNTH in phosphate buffersolution was observed.

2) Inclusion complexation was not achieved through kneading.

3) Freeze-drying permitted the preparation of an amorphous solid phasewith HPβ-CD and PNTNa from their aqueous solution.

1. Inclusion complex formed of element A and element B, wherein elementA is chosen from pantoprazole, a solvate of pantoprazole, a hydrate ofpantoprazole, a salt of pantoprazole with a base, a solvate of a salt ofpantoprazole with a base, a hydrate of a salt of pantoprazole with abase, an enantiomer of pantoprazole, a solvate of an enantiomer ofpantoprazole, a hydrate of an enantiomer of pantoprazole, a salt of anenantiomer of pantoprazole, a solvate of a salt of an enantiomer ofpantoprazole, a hydrate of a salt of an enantiomer of pantoprazole, or amixture thereof; and wherein element B is chosen from cyclodextrin, ahydrate of cyclodextrin, a derivative of cyclodextrin or a mixturethereof.
 2. Inclusion complex according to claim 1 wherein element A ischosen from pantoprazole sodium sesquihydrate (=pantoprazole sodium×1.5H₂O), (−)-pantoprazole sodium sequihydrate, pantoprazole magnesiumdihydrate or a mixture thereof.
 3. Inclusion complex according to claim1, wherein element B is β-cyclodextrin.
 4. Method of preparing aninclusion complex according to claim 1 comprising reacting element Awith element B in a suitable solvent.
 5. Method according to claim 4,wherein the solvent is ethanol.
 6. Inclusion complex prepared by themethod according to claim
 4. 7. Inclusion complex according to claim 1,which is a 1/1 inclusion complex.
 8. Administration form comprising aninclusion complex according to claim 1 together with a suitablepharmaceutical auxiliary.
 9. (canceled)
 10. Method of treating orpreventing a condition treatable or preventable with apyridine-2ylmethylsulfinyl-1H-benzimidazole, which comprisesadministering to a subject prone to or afflicted with a condition apharmaceutically acceptable administration form according to claim 8comprising therapeutically effective amount of the inclusion complex.11. Inclusion complex according to claim 2 wherein element B isβ-cyclodextrin.
 12. Method of preparing an inclusion complex accordingto claim 1 comprising reacting element A with element B in a suitablesolvent.
 13. Method of preparing an inclusion complex according to claim3 comprising reacting element A with element B in a suitable solvent.14. Administration form comprising an inclusion complex according toclaim 2 together with a suitable pharmaceutical auxiliary. 15.Administration form comprising an inclusion complex according to claim 3together with a suitable pharmaceutical auxiliary.